The objective of this research project is to elucidate the photochemical and photobiological mechanisms whereby light (UVA and visible radiation) alone or in the presence of endogenous or exogenous photosensitizers exerts either toxic or therapeutic effects. UVA-induced apoptosis in keratinocytes is associated with EGF receptor internalization and down-regulation without receptor phosphorylation and ubiquitination; also UVA exposure causes delayed and sustained activation of ERK MAP kinase. We have identified the skin lipid cholesta-5,7,9(11)-trien-3 beta-ol (9-DDHC) as the putative agent responsible for UVA-induced skin photosensitivity in Smith-Lemli-Opitz syndrome patients. 9-DDHC generates singlet oxygen and superoxide upon UVA irradiation and is phototoxic to keratinocytes. A2E, a lipid degradation product found in lipofuscin granules deposited in the retina, is photoprotective in the young eye but may be phototoxic in older eyes.